Project Summary The genome of Plasmodium falciparum, the species responsible for most mortality in malaria, is predicted to encode 86-99 protein kinases. Of these, 36 kinases are expressed in the asexual stage of the parasite?s life-cycle, which is responsible for the pathology associated with the disease. Using our proprietary KinaseSeeker technology, we have recently developed assays against 11 Plasmodium falciparum kinases, which are expressed in the asexual stage. Screening a small-molecule kinase inhibitor library has revealed several chemically tractable chemotypes that bind P. falciparum kinases with sub-micromolar affinity. In this application, using a target-based approach, we aim to utilize the chemotypes identified from our screening data, as starting points for development of potent and selective antimalarial agents. In addition, we will use the already commercialized P. falciparum kinase assays, to identify targets for potential kinase inhibitors that have been shown to be active in phenotypic screens against the parasite. The different series of compounds will then be further optimized for potency and selectivity to deliver leads for new antimalarials and improve human health.